Vascular dementia (VaD) is often caused by small vessel arteriosclerotic disease, resulting in ischemic damage to white matter and associated neurodegeneration. Autopsy studies indicate that such changes contribute to the roughly one-third of dementia cases attributed to mixed pathology (MxD), with features of both Alzheimer's disease (AD) and VaD. MxD is particularly prevalent among older Veterans, who have increased risk factors such as metabolic syndrome and cardiovascular disease. However, current clinical trials with AD therapeutics frequently exclude patients with MxD. The interactions of vascular and AD pathology remain elusive, in part due to the dearth of animal models that recapitulate MxD symptomology and pathology. Our project addresses this hurdle, establishing a novel rat model of MxD to elucidate mechanisms associated with vascular complications in AD. We examine the impact of promising therapeutics to prevent AD in the MxD model, focusing on amyloid vaccines, to facilitate the development of combination therapies that can minimize adverse effects of vaccine in MxD patients, such as vasogenic edema and microbleeds. Although asymptomatic in patients with pure AD, the impact on AD patients with VaD is unknown. This proposal will assess: a) if VaD exacerbates AD-associated A? and/or tau pathology; b) differences in peripheral and central inflammation in VaD, AD, and MxD relative to cognitive and/or neurodegenerative parameters; c) whether plasma endothelial microparticles differentiate VaD, AD, and MxD; and d) the effects of known modifiers of AD pathology on MxD. This proposal uses an APP/PS1 transgenic rat model of AD, which develops age-related cognitive deficits, A?/tau deposition, and gliosis. In Aim 1, we examine the impact of this FAD transgene in spontaneously hypertensive stroke-prone (SHR-SP) rats, which exhibits age-related vascular and white matter pathology, neuron loss and progressive cognitive deficits. This MxD model (SHR-FAD) is compared with FAD positive controls and nonTg rats [SHR-SP versus the control strain WKY] for differences in cognition; peripheral and central inflammation, vascular and parenchymal A?, and synaptic loss; and other AD- and VaD- associated pathologies. Plasma and CSF biomarkers corresponding to specific disease pathologies will be identified. Aim 2 investigates interventions that promote amyloid clearance: passive immunization with an anti- A? antibody and curcumin, a pleiotropic A?-binding molecule, to determine their effects on vascular A? deposition and cerebrovascular disease in the SHR-FAD model of MxD. We hypothesize that VaD exacerbates neuroinflammation, synaptic loss and tau accumulation, but reduces neuritic plaques, increasing cerebrovascular amyloid deposition. Increased cerebral penetration of the peripheral anti-A? antibodies and increased plasma levels of cerebrovascular microparticles and cellular adhesion molecules may parallel disruption of the blood brain barrier. Completion of these aims is likely to provide knowledge important for AD trials in patients who also have VaD.